26 research outputs found
An Allosteric Inhibitor of Protein Arginine Methyltransferase 3
PRMT3, a protein arginine methyltransferase, has been shown to influence ribosomal biosynthesis by catalyzing the dimethylation of the 40S ribosomal protein S2. Although PRMT3 has been reported to be a cytosolic protein, it has been shown to methylate histone H4 peptide (H4 1-24) in vitro. Here, we report the identification of a PRMT3 inhibitor (1-(benzo[d][1,2,3]thiadiazol-6-yl)-3-(2-cyclohexenylethyl)urea; compound 1) with IC50 value of 2.5 μM by screening a library of 16,000 compounds using H4 (1-24) peptide as a substrate. The crystal structure of PRMT3 in complex with compound 1 as well as kinetic analysis reveals an allosteric mechanism of inhibition. Mutating PRMT3 residues within the allosteric site or using compound 1 analogs that disrupt interactions with allosteric site residues both abrogated binding and inhibitory activity. These data demonstrate an allosteric mechanism for inhibition of protein arginine methyltransferases, an emerging class of therapeutic targets
Erratum: Unleashing the therapeutic potential of human kallikrein-related serine proteases
Screening of chemical libraries in pursuit of kallikrein-5 specific inhibitors for the treatment of inflammatory dermatoses
Strategy to Target the Substrate Binding site of SET Domain Protein Methyltransferases
Protein
methyltransferases (PMTs) are a novel gene family of therapeutic
relevance involved in chromatin-mediated signaling and other biological
mechanisms. Most PMTs are organized around the structurally conserved
SET domain that catalyzes the methylation of a substrate lysine. A
few potent chemical inhibitors compete with the protein substrate,
and all are anchored in the channel recruiting the methyl-accepting
lysine. We propose a novel strategy to design focused chemical libraries
targeting the substrate binding site, where a limited number of warheads
each occupying the lysine-channel of multiple enzymes would be decorated
by different substituents. A variety of sequence and structure-based
approaches used to analyze the diversity of the lysine channel of
SET domain PMTs support the relevance of this strategy. We show that
chemical fragments derived from published inhibitors are valid warheads
that can be used in the design of novel focused libraries targeting
other PMTs
Correction: Promising Aedes aegypti Repellent Chemotypes Identified through Integrated QSAR, Virtual Screening, Synthesis, and Bioassay
Correction: Promising Aedes aegypti Repellent Chemotypes Identified through Integrated QSAR, Virtual Screening, Synthesis, and Bioassay
Chemical structures of 43 carboxamides.
<p>The most active compounds, with MED < 0.150 µmol/cm<sup>2</sup>, are marked with squares; the least active compounds, with MED > 5 µmol/cm<sup>2</sup>, are marked with circles.</p
Chemical structures of 27 assorted compounds.
<p>The most active compounds are marked with squares.</p
Visualization of relative contributions of molecular fields to the title activity.
<p>Positions discussed in the text are marked with arrows and boxed numbers; the six-membered ring (vertices 7 and 90-94) is encircled for clarity.</p